It is well known that an API in the amorphous state present the pharmaceutical industry with problems that have to be faced during isolation and galenic formulation thereof. Particularly zwitterionic compounds such as Letermovir, known for occurring in different salt forms, provide for many challenges during synthesis and galenic formulation.
Letermovir is known as an highly active drug for addressing HCMV infection and extensively described in Lischka et al., In Vitro and In Vivo Activities of the Novel Anticytomegalovirus Compound Letermovir. Antimicrob. Agents Chemother. 2010, 54: p. 1290-1297, and Kaul et al., First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound Letermovir. Am. J. Transplant. 2011, 11:1079-1084; as well as Marschall et al., In Vitro Evaluation of the Activities of the Novel Anticytomegalovirus Compound Letermovir against Herpesviruses and Other Human Pathogenic Viruses. Antimicrob. Agents Chemother. 2012, 56:1135-1137.
HCMV is a species of virus that belongs to the viral family known as Herpesviridae or herpes viruses. It is typically abbreviated as HCMV and is alternatively known as human herpesvirus-5 (HHV-5). Within Herpesviridae, HCMV belongs to the Betaherpesvirinae subfamily, which also includes cytomegaloviruses from other mammals.
Although they may be found throughout the body, HCMV infections are frequently associated with the salivary glands. HCMV infection is typically unnoticed in healthy people, but can be life-threatening for immuno-compromised subjects, such as HIV infected persons, organ transplant recipients, or newborn infants. In particular, HCMV remains the leading viral cause of birth defects and life-threatening disease in transplant recipients.
Currently approved anti-HCMV drugs target the viral DNA polymerase, pUL54. The known compound Ganciclovir (GCV) acts as nucleoside analogue. Its antiviral activity requires phosphorylation by the HCMV protein kinase, pUL97. In this regard, Cidovir (CDV) as a nucleotide analogue is already phosphorylated and thus active. Foscarnet (FOS) has a different mode of action. It directly inhibits polymerase function by blocking the pyrophosphate binding site of pUL54. However, the above drugs are known to be associated with toxicity and the emergence of drug resistance. Further, its bioavailability remains improvable.
Attempts have been made to develop orally more active, less toxic HCMV antiviral drugs accompanied with a new mode of action by the synthesis and evaluation of benzimidazole ribonucleosides. Drugs of this class were shown to be highly active against HCMV and targeting the viral terminase complex. However, it turned out that such compounds were metabolically unstable.
Furthermore, HCMVs resistant to benzimidazole ribonucleosides have been described where the resistance has been mapped to the viral open reading frames (hereinafter ORFs) UL89 and UL56 (cf. Krosky et al., Resistance of Human Cytomegalovirus to Benzimidazole Ribonucleosides-Maps to Two Open Reading Frames: UL89 and UL56, Journal of Virology, 1998, p. 4721-4728, and Evers et al., Inhibition of Human Cytomegalovirus Replication by Benzimidazole Nucleosides Involves Three Distinct Mechanisms, Antimicrobial Agents and Chemotherapy, 2004, p. 3918-3927).
BAY 38-4766 is another potent and selective inhibitor of HCMV replication and a representative of a novel non-nucleosidic class of anti-HCMV-drugs, the phenylenediamine sulfonamides. It also targets the viral terminase complex. BAY 38-4766 prevents the cleavage of high molecular weight viral DNA concatemers to monomeric genomic lengths. However, the development of such compounds was discontinued.
Furthermore, compound resistant HCMVs have been described, which inter alia contain mutations in the viral ORFs UL56 and UL89 (cf. Buerger et al., A Novel Non-nucleoside Inhibitor Specifically Targets Cytomegalovirus DNA Maturation via the UL89 and UL56 Gene Products, Journal of Virology, 2001, p. 9077-9086).
Other attempts to discover improved anti-HCMV drugs led to the identification of the small-molecular-weight compounds Bay 82-3286 and 3,4 dihydroquinazolines, such as Letermovir.

By contrast to the above-described compounds, the 3,4 dihydroquinazolines as Letermovir block the viral replication without inhibiting the synthesis of progeny HCMV DNA or viral proteins. In fact, Letermovir was shown to act via a mode of action that involves the viral terminase. However, its mode of interaction with the viral terminase complex and its chemical structure is distinct from that of all other thus-far characterized drugs that were known to target the HCMV terminase complex, including BDCRB and BAY 38-4766. While an antiviral activity against rodent cytomegaloviruses was described for all published cleavage/packaging inhibitors, including BDCRB and BAY 38-4766, Letermovir is solely active against the human cytomegalovirus and thus poses high potential as specific human anti-HCMV drug.
The precise chemical name of Letermovir is (S)-{8-Fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid, having the Formula (I) as depicted below

The synthesis of Letermovir is disclosed in US 2007/0191387 A1, exemplary embodiments 14 and 15, pages 40 and 41, paragraphs [0495] to [0505]. Letermovir exhibits a superior anti-HCMV activity in vitro and in vivo and has completed clinical phase IIb trial.
US 2007/0191387 A1 is silent about particular physicochemical properties of Letermovir as regards particle size distribution, specific surface area and pharmaceutically acceptable impurity contents that makes it suitable for solid galenic formulations that are orally administrable.
Preparation of Letermovir is described in WO 2006/133822; Example 11.
WO 2006/133822 is silent about particular physicochemical properties of Letermovir as regards particle size distribution, specific surface area and pharmaceutically acceptable impurity contents that makes it suitable for solid galenic formulations that are orally administrable.
WO 2013/127971 A1 describes sodium and calcium salts of Letermovir and solvates thereof, and use thereof as antiviral agents. WO 2013/127971 A1 is silent about particular physicochemical properties of Letermovir as regards particle size distribution, specific surface area and pharmaceutically acceptable impurity contents that makes it suitable for solid galenic formulations that are orally administrable.
Letermovir inhibits HCMV replication through a specific antiviral mechanism that involves the viral terminase subunit, but that is distinct from that of other compound classes also known to target this enzyme complex (cf. Goldner et al., The Novel Anticytomegalovirus Compound AIC246 (Letermovir) Inhibits Human Cytomegalovirus Replication through a Specific Antiviral Mechanism That Involves the Viral Terminase, Journal of Virology, 2011, p. 10884-10893).
However, the zwitterionic Letermovir bears chemical properties that pose challenges in the field of pharmaceutical chemistry. Following this, isolated Letermovir as zwitterion can be kept in an amorphous state, whereas in the form of acid and basic salts, Letermovir is crystallizable with a limited number of counter ions (see also German Patent Application 10 2012 101 673.9; German Patent Application 10 2012 101 659.3).
Attempts to crystallize the API Letermovir reproducibly in zwitterionic form and to keep it crystallized as a stable polymorph have failed to date. Hence, Letermovir has to be isolated in its amorphous state by sufficient yield and purity while conserving its physicochemical properties, which enable sufficient dissolution characteristics to be implemented in a tablet/capsule formulation for oral administration.
In this regard, only solution formulations of Letermovir are known in the art. However, amorphous Letermovir for intravenously applicable formulations were only completely soluble in water (w/w and w/o ethanol) by adding excess arginine or lysine, or the addition of cyclodextrin in combination with sodium hydroxide.
It was the object of the present invention to obtain fast dissolving solid dosage forms such as tablets and/or capsules of Letermovir in the amorphous state suitable for oral administration. In this context, it was a further object of the invention to obtain oral dosage forms of the solid amorphous API Letermovir for oral administration having sufficient bioavailability.
However, wet granulations based on an aqueous solution of Letermovir and excess arginine by using both, spray and high shear granulation did not result in a tablet/capsule that exhibit sufficient dissolution for immediate release (hereinafter IR). In particular, problems were encountered with respect to isolation of Letermovir as a pure API, purity and/or chemical stability were insufficient in case of most organic solvents including lower alcohols. Thus, against expectation the approach for intravenous formulations by adding arginine was not transferable to tablet/capsule formulations of Letermovir. Arginine did not have a positive effect on the dissolution properties of Letermovir in solid dosage forms as shown in Example 1.
A solubility study conducted by the inventors also confirmed the problematic solubility profile of amorphous Letermovir as in the pH-range of 1 to 7.5 Letermovir solubility varied from 0.4 to >1 mg/ml as shown in Example 2.